Pharmacokinetic drug–drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases. This basic information, therefore, is needed for drug therapy even in veterinary medicine, as multidrug therapy is not rare in canines and felines. The aim of this review was focused on possible drug–drug interactions in dogs and cats. The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and flu- oroquinolones, and down-regulation of enzymes by dexamethasone. A final conclusion based upon the available literatures and author’s experience is given at the end of the review.
Trang 1MINI REVIEW
Possible drug–drug interaction in dogs and cats
resulted from alteration in drug metabolism: A mini
review
Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan
G R A P H I C A L A B S T R A C T
Effects of ketoconazole treatment on intravenous pharmacokinetics of midazolam (CYP3A substrate).
A R T I C L E I N F O
Article history:
Received 7 August 2014
Received in revised form 10 February
2015
Accepted 15 February 2015
Available online 24 February 2015
A B S T R A C T Pharmacokinetic drug–drug interactions (in particular at metabolism) may result in fatal adverse effects in some cases This basic information, therefore, is needed for drug therapy even
in veterinary medicine, as multidrug therapy is not rare in canines and felines The aim of this review was focused on possible drug–drug interactions in dogs and cats The interaction includes enzyme induction by phenobarbital, enzyme inhibition by ketoconazole and
flu-* Corresponding author Tel.: +81 42 367 5770.
Peer review under responsibility of Cairo University.
Production and hosting by Elsevier
Cairo University Journal of Advanced Research
http://dx.doi.org/10.1016/j.jare.2015.02.003
Trang 2Drug–drug interaction
Drug metabolism
Pharmacokinetics
Dogs
Cats
oroquinolones, and down-regulation of enzymes by dexamethasone A final conclusion based upon the available literatures and author’s experience is given at the end of the review.
ª 2015 Production and hosting by Elsevier B.V on behalf of Cairo University.
Kazuaki Sasaki, got his PhD of Veterinary Medicine from United Graduate School of Veterinary Sciences, Gifu University in 2005.
In 2007, he became an Associate Professor of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture,
Technology The research of Dr Sasaki is focused on pharmacokinetics, including drug
(biotransformation and renal excretion) in animals.
Minoru Shimoda, PhD, is a Professor of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture,
Professor in 1982, an Associate Professor in
1993 and a Professor in 2005 of the veterinary department He got PhD from Faculty of Agriculture, University of Tokyo in 1985 The research of Prof Shimoda is focused on pharmacokinetics, including drug absorption, distribution and elimination (biotransforma-tion and renal excre(biotransforma-tion) in animals.
Introduction
Pharmacokinetic drug–drug interaction in drug metabolism
may result in fatal adverse effects In human medicine, patients
treated with antihistaminic drug (terfenadine) and antifungal
(ketoconazole or itraconazole) had Torsades de pointes,
life-threatening ventricular tachycardia in 1991 This was resulted
from the fact that ketoconazole and itraconazole inhibited
CYP3A4 and thereby terfenadine accumulated in the body
[1–4] In 1993, many patients with cancer and herpes zoster,
a viral disease, were died from interactions of an antiviral
(sor-ivudine) with anticancer prodrug, 5-fluorouracil This was due
to the inactivation of an enzyme catalyzing the metabolism of
5-fluorouracil by co-administration of sorivudine[5–7] Since
the abovementioned medical accidents, researchers have paid
much attention to pharmacokinetic drug–drug interaction
originated from the alteration in drug metabolism in human
medicine
Alterations in drug metabolism due to pharmacokinetic
drug–drug interaction are well recognized either as enzyme
induction or as enzyme inhibition So far, many drugs have
been demonstrated to cause alteration in drug metabolism
in human medicine Phenobarbital has been used as a CYP inducer in many studies [8–11] and ketoconazole is well characterized as a potent CYP inhibitor [12–15]
In veterinary medicine, pharmacokinetic drug–drug inter-action in drug metabolism is an important subject, because multidrug therapy is commonly used for treatment of small animals including dogs and cats Since there were big differ-ences in drug metabolism, it is unclear whether the interactions that have been demonstrated in humans are substantial to ani-mal species
Basically, CYP1A1/2, 2C9, 2C19, 2D6, and 3A4 isoforms played important roles in drug metabolism in humans Similar isoforms have been also found in dogs and cats Dogs have CYP1A1/2, 2C21, 2D15 and 3A12 isoforms, whereas, CYP1A1/2, 2D6, 3A131 and 3A132 have been iden-tified in cats, although they do not have tolbutamide hydrox-ylation activity, which is related to CYP2C9 activity in humans This fact suggests that serious drug–drug interaction
in drug metabolism catalyzed by CYPs can happen in dogs and cats Although the information regarding such kind of interac-tion is not sufficient in veterinary medicine, it is gradually increasing in dogs and cats
Scope of the review This review introduces drug–drug interaction in drug metabo-lism in dogs and cats as follows: First, enzyme induction of phenobarbital and other drugs in dogs is described Then, inhi-bitory effects of azole antifungals, fluoroquinolones, and other drugs on CYP activities in dogs and cats were discussed Finally, down-regulating effects of dexamethasone on CYP activities in dogs are evaluated The literature search was con-ducted using PubMed
Enzyme induction
The mechanisms by which enzymes are induced include the fol-lowing (1) Medicines (inducers) bound to receptor (known as receptor-type transcriptional factors located in cytoplasm of hepatocytes) (2) Then the receptor was activated to allow its translocation to nucleus (3) The translocated receptor bound
to its response element of DNA (4) The level of mRNA was correlated to enzyme expression (5) The increase of mRNA levels results in increases of enzymes [16] Fig 1 shows the mechanism by which CYP1A is induced In cytoplasm, the well defined receptors include aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane
X receptor (PXR) The AhR was related to the induction of CYP1A and CAR and PXR were responsible for induction
of CYP2B, 2C, and 3A subfamilies
Trang 3Enzyme induction by phenobarbital
As shown inTable 1several drugs have been demonstrated to
induce various CYPs and UDP-glucuronosyltransferase in
humans Among them, phenobarbital has been found to
induce some CYPs in dogs[17–20] The drug induces enzyme
through activating CAR Graham et al.[17]examined
induc-tion of CYP1A, 2B, and 3A after multiple subcutaneous
injec-tion of phenobarbital (14 days, 10 – 30 mg/kg/day) in beagle
dogs They found 10- and 2-fold increase in CYP2B and 3A
activities in hepatic microsomes, whereas CYP1A activities
were not affected Hojo et al [18] determined the effects of
phenobarbital in its clinical dosage regimen (5 mg/kg/day
p.o., bid) on CYP activities in dogs treated for 35 days The
total body clearance (CL) of a CYP3A substrate, antipyrine,
was thereafter evaluated after intravenous injection They
found that the CL was increased <3-fold following 9th day
of the treatment, and afterward remains steady (Fig 2)
They also examined the hepatic microsomal activities of
CYP1A, 2C, 2D and 3A after the same course of treatment
(35th day) While the activities of CYP2C and CYP3A were
increased 2-and 4-fold (compared to control), the activities
of CYP1A and 2D were not affected
Effects of the oral phenobarbital treatment (5 mg/kg/day
p.o., bid for 30 days) on intravenous pharmacokinetics of
theophylline (a CYP1A substrate), phenytoin (a CYP2C
substrate) and quinidine (a CYP3A substrate) have been exam-ined in beagle dogs The pharmacokinetics of phenytoin and quinidine were affected by the phenobarbital treatment, whereas that of theophylline was not affected as shown in Fig 3 The intrinsic clearances of phenytoin and quinidine (calculated from multiplying total body clearance by unbound fraction in plasma) were increased by 2- and 3-fold, respectively
As obvious from the above, the CYP induction by pheno-barbital was substantial Therefore, there were high possibili-ties of drug–drug interaction with medicines that are mainly metabolized by CY2C or 3A in diseased dogs suffering from epilepsy
Phenobarbital also induces UDP-glucuronosyltransferase
in dogs Oguri et al demonstrated 3-fold increase in morphine glucuronidation in hepatic microsomes obtained from dogs treated with phenobarbital [21] As NSAIDs were mainly eliminated from the body by biotransformation via glu-curonidation, we, therefore, examined the effects of the pheno-barbital treatment (5 mg/kg/day p.o., bid) on pharmacokinetics of carprofen after intravenous and oral administration in dogs As a result, the total body clearance
of carprofen increased by more than twice, compared to prior treatment Although oral bioavailability of the drug was not affected, the oral AUC was nearly half compared to prior treatment These findings indicate that phenobarbital could
mRNA
mRNA increase of enzyme
arylhydrocarbon receptor (AhR)
heat shock protein drug
cytoplasm
nucleus
AhR nuclear translocator
transcriponal
control domain
Fig 1 Mechanism of CYP1A induction Drugs (inducers) binds
to AhR-heat shock protein complex in hepatocytes cytoplasm
Then the complex is activated and enters inside the nucleus The
complex releases heat shock protein and binds to a transporter
called AhR nuclear translocator Then the complex binds to its
response element of DNA, and the level of mRNA that relates to
expression of enzymes increases Finally, enzymes are induced
Table 1 Drug inducing enzyme activities in humans
(ethanol)
0 1.0 2.0
Days from the start of phenobarbital
treatment
Fig 2 Antipyrine clearance during phenobarbital treatment in dogs Dogs were orally administered phenobarbital at 5 mg/kg twice a day for 30 days, during which antipyrine was intravenously injected at 5 mg/kg, and its clearance values were estimated Each value and vertical bar represent mean and SD, respectively (n = 5)
Trang 4induce UDP-glucuronosyltransferase much enough suggesting
drug–drug interaction for remedies whose main elimination
route is glucuronidation
Phenobarbital is also a drug of choice for cats with epilepsy
[22–24] There were, however, few studies on enzyme induction
by phenobarbital in cats Maugras and Reichart [25] found
slight increase in CYP levels in microsomes from cats treated
with phenobarbital, compared to control ones Truhaut et al
[26] found no induction of CYP following phenobarbital
administration These findings may suggest that phenobarbital
causes minimal cytochrome P450 enzyme induction in cats,
and therefore drug–drug interactions mediated by
phenobarbi-tal are unlikely to occur in cats
Cochrane et al.[27]compared phenobarbital
pharmacoki-netics at steady state of oral administration with that after
sin-gle oral administration in cats As phenobarbital is mainly
eliminated from the body via oxidation catalyzed by CYP2C,
the oral clearance at steady state should be higher than that
after single dosing, if induction of CYP2C is substantial
They, however, found no difference in the clearance between
steady state and single dosing This may suggest that drug–
drug interactions mediated by phenobarbital are unlikely in
cats
Enzyme induction by other drugs
Among the medicines in Table 1, the inducing effects of
omeprazole and rifampicin on CYP enzymes in dogs were
pre-viously reported Nishibe and Hirata[28]examined the
induc-ing effects of omeprazole and rifampicin usinduc-ing primary culture
of dog hepatocytes They found significant induction of CYP1A by omeprazole and CYP3A by rifampicin Graham
et al [17]demonstrated 3-fold increase in CYP3A activities
in dog microsomes after oral administration of rifampicin These results may suggest that drug–drug interaction mediated
by abovementioned remedies can happen in dogs
Enzyme inhibition
Since drug–drug interaction mediated by enzyme inhibition increases accumulation of medicines, potent inhibitors may result in fatal adverse effects of co-administered drugs It is, therefore, generally recognized that much attention should
be paid to that type of interaction
Enzyme inhibition by ketoconazole
Ketoconazole is an azole antifungal drug, which is known to inhibit CYP3A potently in humans Its inhibitory effects on CYP activities have been investigated in vitro and in vivo in dogs and cats Kuroha et al.[29]demonstrated that ketocona-zole could inhibit competitively midazolam 10-hydroxylation catalyzed by CYP3A with 24 nM of Kivalue, using dog hep-atic microsomes This Ki value was estimated based on unbound concentration of ketoconazole in the assay system This 24 nM corresponds to 83 nM of its total concentration [29] The 83 nM is comparable to those obtained from humans (32–180 nM [30–35] This fact suggests that ketoconazole inducing CYP mediated drug–drug interaction may be serious
in dogs as found in humans[1–4]
4 2
Time (h)
10
1 after treatment
before treatment
Phenytoin 10
1
4 2
Time (h)
after treatment
before treatment
Theophylline
4 2
Time (h)
0.01 0.1 1 10
after treatment
before treatment
Quinidine
Fig 3 Effects of phenobarbital treatment on intravenous pharmacokinetics of theophylline (CYP1A substrate), phenytoin (CYP2C substrate) and quinidine (CYP3A substrate) in dogs Dogs were orally administered phenobarbital at 5 mg/kg twice a day for 30 days or
50 days and then pharmacokinetics of theophylline (5 mg/kg), phenytoin (5 mg/kg) and quinidine (1 mg/kg) were examined following intravenous injection Each value and vertical bar represent mean and SD, respectively (n = 5)
Trang 5Fig 4shows the effects of ketoconazole on
pharmacokinet-ics of midazolam following intravenous injection Dogs were
treated with ketoconazole (20 mg/kg p.o., bid) for 30 days
As shown inFig 4, ketoconazole treatment affected evidently
the midazolam pharmacokinetics The midazolam total body
clearance was decreased by less than one-third at the end
com-pared to prior treatments This finding suggests that the
inhi-bitory effect on CYP3A may be quite potent in dogs
Kukanich et al have found that 5 day treatment with oral
ketoconazole at 12.25 mg/kg would increase the mean
resi-dence time of midazolam approximately twice[36]
The inhibitory effects of ketoconazole on CYP3A activities
affected also the pharmacokinetics of other drugs that were
eliminated by metabolism and catalyzed by CYP3A Kuroha
et al has demonstrated that the total body clearance of
quini-dine was decreased from 8.4 to 2.7 ml/min/kg by ketoconazole
treatment at clinical dosage[37] They also demonstrated that
the total body clearance of nifedipine was decreased by
approximately 50% compared to prior treatment
Additionally, they found twice increase in the oral
bioavail-ability of nifedipine [38] Kukanich et al [39] found that
Cmax of methadone after oral administration was increased
to more than 30-fold by the co-administered, ketoconazole
Cyclosporine, an immunosuppressant, was used for
treat-ment of canine atopic dermatitis The drug was metabolized
by CYP3A and possible drug–drug interaction with
ketocona-zole was evaluated[40–42] Dahlinger et al.[41]showed that a
3.4 mg/kg dose of cyclosporine with ketoconazole gave similar
blood levels of cyclosporine (400–600 ng/mL) compared to
14.5 mg/kg cyclosporine alone D’mello et al.[42]found that
the systemic clearance of cyclosporine was decreased from
7.0 ml/min/kg to 2.5 ml/min/kg by ketoconazole Because of
the inhibitory effect, the co-administrations of ketoconazole
with cyclosporine have been recommended, which in turn
decreases the therapeutic cost[43–45]
CYP3A inhibition by ketoconazole has also been reported
in cats Shah et al.[46]showed in his in vitro experiment using
feline hepatic microsomes that ketoconazole can inhibit
midazolam 10-hydroxylation in a non-competitive manner
They estimated the inhibition constant of ketoconazole to be
2 lM Although this value might be quite low to cause drug–
drug interaction, it is more than 20-fold higher compared to
the estimated value in dogs [29] Because of this fact,
ketoconazole related drug–drug interaction may occur at smal-ler extent compared with those in dogs and humans Shah et al [46]have demonstrated that the decrease in quinidine clearance
by ketoconazole treatment was less than a half in cats However, they showed a time-dependent decrease in midazo-lam 10 hydroxylation by pre-incubation of feline microsomes with ketoconazole This suggests that ketoconazole has a mode
of mechanism based inhibition in cats, although the mode has not been reported in dogs and humans McAnulty and Lensmeyer[47] showed in his study the inhibitory effects of ketoconazole on cyclosporine pharmacokinetics, which can
be implied from two times maximum cyclosporine blood con-centration in cats treated orally with ketoconazole
Ketoconazole can inhibit CYP activities other than CYP3A In this context, Kuroha et al.[48]showed the inhibi-tion of CYP1A, 2C, and 2D activities using 7-ethoxyresorufin O-deethylation, tolbutamide methyl hydroxylation, and bufur-alol 10-hydroxylation, respectively The drug inhibited CY1A and 2C activities with 10.6 and 17.0 lM of Kivalues, respec-tively These values may be small enough to cause drug–drug interaction, although they are quite higher than that for CYP3A activities
Enzyme inhibition by fluoroquinolones
It was reported that fluoroquinolones could inhibit CYP1A activities[49–53] Among them, ciprofloxacin, enoxacin, and norfloxacin can cause drug–drug interaction with xanthine derivatives and potentiate its toxicity in human medicine [54–58]
Enrofloxacin, ciprofloxacin, ofloxacin, orbifloxacin, and norfloxacin inhibit CYP1A activities in dogs Regmi et al [53]demonstrated that the aforementioned fluoroquinolones could inhibit 7-ethoxyresorufin O-deethylation in a non-com-petitive manner in hepatic microsomes obtained from dogs The Ki values were ranged from 0.7 for ciprofloxacin to
10 mM for ofloxacin; the values suggest that the inhibitory effects are quite small On the other hand, ciprofloxacin, oflox-acin, and orbifloxacin showed mechanism based inhibition Although it was not reported that ciprofloxacin and ofloxacin could have mechanism based inhibition in humans, and oflox-acin inhibits CYP1A activities by this manner in hepatic microsomes obtained from humans[59]
Drug–drug interaction of fluoroquinolones with theo-phylline has been reported in dogs Intorre et al examined intravenous injection of enrofloxacin on steady stale levels of theophylline following oral administration in dogs[60] They found increases in the steady state blood theophylline concen-trations; due to enrofloxacin treatment This could be implied from the mechanism based inhibition of enrofloxacin metabo-lite, ciprofloxacin Enrofloxacin itself does not have this type
of inhibitory mode and reversible inhibition is quite small [53] Although ofloxacin shows the mode of mechanism based inhibition, it does not affect theophylline pharmacokinetics in dogs [61] Furthermore, levofloxacin does not affect theo-phylline pharmacokinetics in humans[62], although some flu-oroquinolones would affect
In cats there were no reports describing the inhibitory effects of fluoroquinolones on CYP1A activities In our labo-ratory, we have examined this effect in cats and noticed that enrofloxacin, ofloxacin, norfloxacin, and orbifloxacin could
Time (h)
'D\
'D\
%HIRUH
Fig 4 Effects of ketoconazole treatment on intravenous
pharmacokinetics of midazolam (CYP3A substrate) Dogs were
orally administered ketoconazole at 20 mg/kg twice a day for
30 days, during which midazolam was intravenously injected at
0.5 mg/kg Each value and vertical bar represent mean and SD,
respectively (n = 5)
Trang 6inhibit 7-ethoxyresorufin O-deethylation in a competitive
man-ner, whereas, ciprofloxacin inhibited the enzyme by a
non-competitive manner The obtained Ki values ranged from
0.12 mM (for norfloxacin) to 1.2 mM (for ofloxacin)
Although these values are smaller than those obtained in dogs,
the reversible inhibitions may not result in a drug–drug
inter-action with other medicines, which are substrates for CYP1A
enzyme We also found a mechanism based inhibition for
ciprofloxacin and ofloxacin in cats Similar to dogs[60],
enro-floxacin may cause a drug–drug interaction with theophylline
in cats
Fluoroquinolones can also inhibit CYP3A activities in
humans [52,63], rats [52], and chickens [64] Enrofloxacin,
ciprofloxacin, ofloxacin, norfloxacin, and orbifloxacin,
how-ever, did not affect Michaelis–Menten kinetics of 10
-hydrox-ylation of midazolam using dog hepatic microsomes
Additionally, enrofloxacin and ofloxacin did not affect the
pharmacokinetics of a CYP3A substrate, quinidine, following
intravenous injection in dogs[65] Although we examined the
effects in cats, the results were almost the same as reported
in dogs[65] Therefore, fluoroquinolones may not be
responsi-ble for a CYP3A mediated drug–drug interaction in dogs and
cats
Enzyme inhibition by other drugs
Many drugs other than ketoconazole and fluoroquinolones
may inhibit CYP activities in dogs and cats, same as in
humans Aidasani et al.[66]evaluated the CYP reversible
inhi-bition of many drugs used in veterinary medicine using canine
hepatic microsomes As a result, they found that ondansetron
and miconazole were potent inhibitors for CYP1A; vincristine
is a potent inhibitor for CYP2C; and loperamide, vincristine,
clomipramine, and fluoxetine were potent inhibitors for
CYP2D On the other hand, they reported that loperamide,
miconazole, and cyclosporine A were potent CYP3A inhibi-tors The inhibitory effect of erythromycin and cimetidine was not so strong, although they are potent inhibitors in humans Mills et al [67]have found that fluvoxamine could inhibit canine CYP1A activities with Ki value = 3 lM Additionally, they declare that fluoxetine and clomipramine were potent inhibitors for CYP2C and 2D Table 2 shows those medicines that could inhibit canine CYP activities
In cats Shah et al.[46]examined the inhibitory effects of the aforementioned drugs They demonstrated that both drugs inhibited non-competitively 10-hydroxylation of midazolam with Kivalue of approximately 3 mM This value suggests that the inhibitory effects of erythromycin and cimetidine on CYP3A activities were quite small and hence may not cause drug–drug interaction with CYP3A substrates in cats Medical herbs may also inhibit CYP activities in dogs Liu
et al.[68]and Abd El-Aty et al.[69]have found that the vola-tile extracts from Nigella sativa seeds and decursin and decursi-nol angelate can inhibit CYP1A activities in hepatic microsomes obtained from dogs
Drug induced down-regulation of enzymes
It is well known that CYPs are down-regulated by diseases, including renal failure[70,71], infection[72,73]and inflamma-tion[74,75] However; down-regulation induced by drugs was not known well and only few reports were recorded Zhang
et al.[76]examined the Michaelis–Menten kinetics of reactions catalyzed by CYPs using hepatic microsomes obtained from dogs treated with oral dexamethasone at clinically relevant doses (0.25 and 0.75 mg/kg) for 5 days They found dose-de-pendent decreases in the reaction of bufuralol hydroxylation (catalyzed by CYP2D) and midazolam 4-hydroxylation (cat-alyzed by CYP3A), and the decreases were due to a decrease
in maximal velocity but not Km values as shown in Fig 5
Table 2 Drugs inhibiting enzyme activities in dogs
0.8
0.6
0.4 0.2
Midazolam (µM)
Control
0.25 mg/kg
0.75 mg/kg
Bufuralol (µM)
0.18
Control
0.25 mg/kg
0.75 mg/kg
0.12
0.06
Fig 5 Effects of dexamethasone treatment on Michaelis–Menten kinetics of midazolam 4-hydroxylation and bufuralol hydroxylation in hepatic microsomes from dogs treated with dexamethasone Dogs were orally administered dexamethasone at 0.25 or 0.75 mg/kg/day for
5 days Each value and vertical bar represent mean and SD, respectively (n = 5)
Trang 7They also examined the inhibitory effects of dexamethasone on
midazolam 4-hydroxylation and showed a small competitive
inhibition with Kivalue of 200 lM From these data, Zhang
et al concluded that the decreases in CYP2D and 3A activities
in dogs are due to down-regulation caused by dexamethasone,
although steroids are well known as CYP3A inducer[77–79]
In the same study, the effects of dexamethasone treatment
on Michaelis–Menten kinetics of midazolam 4-hydroxylation
were also examined in rats Maximal velocities of the reaction
were increased by the treatment schedule set at a high dose
(48 mg/kg for 5 days), suggesting CYP3A induction
However, the maximal velocities of the reaction were
decreased by treatment at a low dose regimen (0.75 mg/kg
for 5 days), suggesting down-regulation of CYP3A These data
may suggest that dexamethasone down-regulates CYP3A at a
clinically relevant dose in various animal species
The down regulating effects of dexamethasone may result
in drug–drug interaction with substrates metabolized by
CYP2D or CYP3A Zhang et al.[80]examined the effects of
dexamethasone treatment (0.25 and 0.75 mg/kg/day for
5 days) on intravenous pharmacokinetics of quinidine in dogs
Since dexamethasone decreased plasma levels of alpha 1-acid
glycoprotein (the main binding protein for quinidine) they
ana-lyzed the unbound concentration–time curves As obvious
fromFig 6, the elimination of quinidine became slower in a
dose-dependent manner Intrinsic clearance was approximately
a half, compared to prior treatment This indicates that the
down-regulating effect of dexamethasone can cause drug–drug
interaction with quinidine in dogs
Conclusions
So far, many drugs have been demonstrated to cause alteration
in drug metabolism in human medicine In veterinary
medi-cine, however, only some drugs have been investigated as
described in this review More advanced medical care is
recom-mended to be used in dogs and cats This may accelerate
mul-tidrug therapy in these animal species, using many kinds of
drugs like in humans This may result in increased possibilities
of drug–drug interaction that induces fatal toxicity of the drug
The author expects much more investigations on this area in
future
Conflict of interest The authors have declared no conflict of interest
Compliance with Ethics Requirements
This article does not contain any studies with human or animal subjects
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10
100
0
Time (h)
0.75 mg/kg
0.25 mg/kg before
treatment
Fig 6 Effects of dexamethasone treatment on intravenous
pharmacokinetics of quinidine (CYP3A substrate) in dogs Dogs
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kg/day for 5 days Each value and vertical bar represent mean and
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